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Abstract & Commentary
Synopsis: Hong Kong investigators report that SARS is a triphasic illness, at least in patients given corticosteroids and ribavirin.
Source: Peiris JS, et al. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: A prospective study. Lancet. Published online May 9, 2003. http://image.thelancet.com/extras/03art4432web.pdf.
Peiris and colleagues prospectively studied 75 patients with severe acute respiratory syndrome (SARS) admitted to the United Christian Hospital in Hong Kong. They were among the 321 residents of the Amoy Gardens housing estate who developed this syndrome.
The mean age of the patients was 39.8 ± 12.2 years. All 75 patients were febrile at presentation, 65% had chills with 56% having rigors, 68% myalgia, 29% cough, 11% sore throat, 4% shortness of breath, 15% headache, and 1% diarrhea. The initial chest x-ray was abnormal in 71%. Abnormalities seen on plain radiographs or CT scans in varying proportions included both single- and multi-zonal involvement, focal ground-glass opacification, and consolidation.
The WBC was usually normal, but 75% had total lymphocyte counts < 1000/mm3, and 37% were thrombocytopenic. The median lymphocyte counts decreased from 800/mm3 on admission to 400/mm3 on day 21. Modest elevation of serum transaminases, LDH, and creatine kinase were frequent.
All patients were managed with a regimen that included amoxicillin/clavulanate and azithromycin, with ribavirin and hydrocortisone given "as soon as the diagnosis of SARS was established."
The ribavirin was given intravenously in a dose of 8 mg/kg every 8 hours for 14 days. Hydrocortisone was given in a dose of 200 mg IV every 8 hours for 10 days, followed by a prednisolone taper during the next 11 days, with 500 mg IV pulses of methylprednisolone daily for clinical worsening.
With this regimen, almost all patients initially became afebrile, but fever recurred at a mean of 9 days; in 10 there was evidence of a nosocomial bacterial infection. Approximately three-fourths developed watery diarrhea after a mean of 7.5 days. Radiographic worsening was observed at a mean of 7.4 days in 80% of the patients, and desaturation to less than 90% occurred in 44%. At least 15 patients developed ARDS and required mechanical ventilation. At the time of writing, 5 (7%) of the patients had died and 13 (17%) were receiving intensive care. Increasing age and chronic hepatitis B virus infection were independent risk factors for the development of severe respiratory disease.
All but 7% developed IgG antibody to SARS viral antigens at a mean of 20 days. SARS-associated corona-virus RNA was detected in nasopharyngeal aspirates by RT-PCR in 32% at initial presentation and in two-thirds on day 14. Viral RNA was detected in stool samples collected at 14 days in 97% of 67 and was detected in 42% of urine samples at 15 days. The geometric mean nasopharyngeal viral RNA titer increased from 2.3 × 105 copies/mL on day 5 to 1.9 × 107 copies/mL on day 10. The titer then decreased to 9.8 × 104 copies/mL on day 15.
Comment by Stan Deresinski, MD, FACP
Peiris et al indicate that these patients exhibited a triphasic pattern with an initial flu-like febrile illness improving after a few days. Then, during the second week, the fever frequently recurred, patients commonly had diarrhea, and oxygen desaturation developed and viral load peaked but then began dropping contemporaneously with seroconversion.
This extensive experience provides valuable information concerning the clinical course of SARS. The generalizability of the data must, however, be questioned for a number of reasons.
It is suggested that the route of infection in this cohort may have been by the fecal-oral route (although more recent epidemiologic investigation has uncovered a potential airborne route of spread at the Amoy Gardens). It is possible that infection occurring by the respiratory route may have different clinical characteristics. One finding that suggests this may be true is that only 29% of patients coughed at the time of presentation.
The major reason to suspect, however, that these data may not be representative is the fact that all these patients received antibiotics, ribavirin, and corticosteroids, which may have altered the course of the illness either favorably or unfavorably (or some combination of the 2). Thus, it is very likely that the initial temporary reduction of fever was the result of corticosteroid administration, which may also have resulted in the drop in lymphocyte counts from already low levels at presentation. The increase in viral load may also have been the result of immunosuppression resulting from corticosteroid administration. Peiris et al conclude that the subsequent decrease in viral titers at a time when the pulmonary disease was worsening suggests that the latter is the consequence of immunopathological damage, rather than direct cytolytic effect. If so, it occurred in the face of significant corticosteroid doses.
Corticosteroid therapy may also have contributed to an apparently high incidence of nosocomial infection in these patients. The use of ribavirin is also worrisome here. In vitro studies indicate that this drug has little or no in vitro activity against the SARS coronavirus. However, Peiris et al argue that ribavirin may exert an immunomodulatory effect, perhaps by facilitating a Th-1 response. However, given its potential toxicity, it is difficult to justify its use in SARS outside a randomized, controlled trial setting.
Finally, the majority of patients developed diarrhea during their hospitalization. Peiris et al suggest that this may be the result of enteric infection by the SARS coronavirus. It seems at least as likely, however, that the diarrhea was the consequence of the administration of amoxicillin/clavulanate and azithromycin to these patients.
This paper is a useful contribution to our understanding of SARS. It will be of interest, however, to see the results observed in a similarly large cohort in the absence of the pharmacological interventions used here.